Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2017; 23(20): 3655-3663
Published online May 28, 2017. doi: 10.3748/wjg.v23.i20.3655
M2-like Kupffer cells in fibrotic liver may protect against acute insult
Qing-Fen Zheng, Li Bai, Zhong-Ping Duan, Yuan-Ping Han, Su-Jun Zheng, Yu Chen, Jian-Sheng Li
Qing-Fen Zheng, Jian-Sheng Li, Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Li Bai, Zhong-Ping Duan, Su-Jun Zheng, Yu Chen, Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
Yuan-Ping Han, Center for Growth, Metabolism and Aging, Key Laboratory for Bio-Resource and Eco-Environment, College of Life Sciences, Sichuan University, Chengdu 610014, Sichuan Province, China
Yuan-Ping Han, National Key Laboratory of Biotherapy, Sichuan University, Chengdu 610014, Sichuan Province, China
Author contributions: Zheng QF, Bai L and Duan ZP contributed equally to this work; Zheng QF and Bai L performed the majority of experiments and wrote the paper; Duan ZP analyzed the data and revised the paper; Han YP, Zheng SJ and Chen Y participated equally in the treatment of animals; Li JS designed the research.
Supported by Special Fund of Clinical Medicine, Beijing Municipal Administration of Hospitals, No. XM201308; Ascent Plan of Beijing Municipal Administration of Hospitals, No. DFL20151601; YouAn fund for liver diseases and AIDS, No. YNKT20160012; startup fund from Sichuan University, Beijing Municipal Science and Technology Commission, No. Z131107002213019 and No. Z151100004015066; and the Basic-Clinical Cooperation Project of Capital Medical University, No. 17JL47.
Institutional review board statement: This study was reviewed and approved by the Capital Medical University Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Capital Medical University (AEEI-2014-071).
Conflict-of-interest statement: The authors declare that they have no conflict of interest related to this study.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Jian-Sheng Li, Professor, Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou 450052, Henan Province, China. lijiansheng@medmail.com.cn
Telephone: +86-371-66862052 Fax: +86-371-66862052
Received: January 10, 2017
Peer-review started: January 10, 2017
First decision: February 9, 2017
Revised: February 21, 2017
Accepted: March 30, 2017
Article in press: March 30, 2017
Published online: May 28, 2017
Processing time: 137 Days and 15 Hours
Abstract
AIM

To investigate the mechanism of hepatoprotection conferred by liver fibrosis through evaluating the activation phenotype of kupffer cells.

METHODS

Control and fibrotic mice were challenged with a lethal dose of D-GalN/lipopolysaccharide (LPS), and hepatic damage was assessed by histology, serum alanine transferase (ALT) levels, and hepatic expression of HMGB1, a potent pro-inflammatory mediator. The localization of F4/80 (a surrogate marker of KCs), HMGB1, and type I collagen (Col-1) was determined by immunofluorescence staining. The phenotype of KCs was characterized by real-time PCR. KCs isolated from control or fibrotic mice were challenged with LPS or HMGB1 peptide, and HMGB1 translocation was analyzed.

RESULTS

Liver fibrosis protected mice against D-GalN/LPS challenge, as shown by improved hepatic histology and reduced elevation of ALT compared with the normal mice treated in the same way. This hepatoprotection was also accompanied by inhibition of HMGB1 expression in the liver. Co-localization of F4/80, HMGB1, and Col-1 was found in fibrotic livers, indicating the close relationship between KCs, HMGB1 and liver fibrosis. KCs isolated from fibrotic mice predominantly exhibited an M2-like phenotype. In vitro experiments showed that HMGB1 was localized in the nucleus of the majority of M2-like KCs and that the translocation of HMGB1 was inhibited following stimulation with LPS or HMGB1 peptide, while both LPS and HMGB1 peptide elicited translocation of intranuclear HMGB1 in KCs isolated from the control mice.

CONCLUSION

M2-like Kupffer cells in fibrotic liver may exert a protective effect against acute insult by inhibiting the translocation of HMGB1.

Keywords: Liver fibrosis; Injury resistance; Kupffer cell activation; high-mobility group box 1; Translocation

Core tip: The hepatoprotective effect conferred by liver fibrosis against acute liver injury is an interesting phenomenon, which has not yet been fully characterized. In the present study, we dissected the underlying mechanism of acute injury in the setting of liver fibrosis through investigating the correlation between KC activation and HMGB1 translocation. Our study showed that liver fibrosis protects mice against D-GalN/LPS challenge, and M2-like KCs in the fibrotic liver may exert a protective effect by inhibiting the translocation of HMGB1, a potent pro-inflammatory mediator.